There are several problems associated with the treatment of STI, sexually transmitted infections. The overuse of systemic treatment with active agents, such as antibiotics, has led to development of resistance and the diversity of the diseases, which leads to the need for several treatments with different actives that increase the risk for maltreatment. The difficulty of diagnosing is another issue that can make therapies inefficient. Local treatment has so far been inefficient. The reason for the inefficacy of local treatment is lack of effective local agents. There are numerous germicidal agents available but the concentration to generate an antibacterial effect is about the same as toxic concentrations. One exception is hydrogen peroxide, which is endogenous and nontoxic at low levels. So far attempts to cure vaginal infections with hydrogen peroxide have failed due to effects of peroxide degrading enzymes, catalases. There is also a need for an inexpensive short term treatment since STI is very frequent in development countries with small resources and few medical providers. Development and manufacture of new antibiotics is expensive, while the present invention can be performed locally at a reasonable cost.
Peroxides, and in particular hydrogen peroxide, are described in the literature as being active against anaerobic bacteria involved in vaginal and urinary tube infections represented but not limited to G. vaginosis, N. gonorrhea. The activity is rapid, Block, S. Lea & Febiger 1983, p 243, claims 2 log reduction in 7 seconds. However, this is valid only for laboratory conditions. In the clinical situation there are enzymes degrading hydrogen peroxide present in the form of catalases. The catalases are generated partly by plasma cells available in the infected area but also by pathogens such as G. vaginalis and N. gonorrhea. The catalases are not active at low pH, under pH 4 and have very little activity between pH 4 and 5. The pH in a healthy vagina is about 4.5 or lower and in an infected ditto over pH 5. In men the infection is located in the mucosa of the urethra. The pH here is somewhat higher, about 5 to 8. The present invention solves this problem by providing a pH below 4.5 during the treatment phase allowing eradication of pathogens by hydrogen peroxide. As soon as the pathogens are killed, lactobacteria will be established in the area and pH will be kept low by the present invention.
There have been attempts to develop products including hydrogen peroxide for the treatment of vaginal infections. In clinical use, such as in a body cavity, the activity is rapidly destroyed by enzymes that degrade hydrogen peroxide, e.g. catalases. Since catalases are not active at a pH below 4 and have a much reduced activity in the pH range of 4 to 5 attempts have been made to develop products containing a peroxide source, including hydrogen peroxide, for treatment of vaginal infections by including a pH reducing polyacrylic acid (U.S. Pat. No. 5,741,525). However, such a product is likely to have insufficient storage stability with regard to hydrogen peroxide, is associated with difficulties in effective self-administration and does not to fill the entire cavity following administration leaving untreated areas from which the infection can spread. Furthermore, if unstabilized hydrogen peroxide is exposed to organic matter an auto-oxidation process starts degrading the content of hydrogen peroxide to water and oxygen in seconds or minutes. This will decrease the efficacy and duration of the effect of hydrogen peroxide. The present invention solves these problems by stabilization and auto-oxidation is less likely to occur or occur at a much lower speed.
In U.S. Pat. No. 7,709,026, Bologna et. al., the use of a “hydrogen peroxide” source in combination with a polymer for regulation of the release of peroxides described. As for the previous patent there is no record on stabilization of hydrogen peroxide. No data on the antimicrobial effect is revealed but it should be low since the release of hydrogen peroxide is low, only 26 mM is claimed, and when diluted in the vaginal fluid the concentration of hydrogen peroxide should be further reduced. Since 20 mM or more is required for inhibition of several species even at low pH the product should not be effective. Attassi F., Servin, A., “Individual and co-operative roles of lactic acid and hydrogen peroxide . . . .” FEMS Microbiological letter 394 (2010) 29-38. The present invention solves this problem by releasing instantly, such as 88 mM of hydrogen peroxide at a pH, less than 5, where the catalases are ineffective. This product is also associated with difficulties in effective self-administration and does not to fill the entire cavity following administration leaving untreated areas from which the infection can spread.
Local treatment of diseases in body cavities such as vagina, urethra, ear, anus and the nasal cavity in general require treatment of the entire area in the body cavity. If only a part of the area is treated local infections and inflammations may remain partly untreated. Intra-cavital preparations such as gels, ointments, vagitories/suppositories and tablets have the draw back that only a minor part of the surface is treated. In the case of systemic delivery of active compounds by administration in body cavities the lack of surface coverage means that only a small and from time to time varying area is exposed. This will lead to an unpredictable drug uptake and to a variation in the biological response and medical effect, and risk for resistance development. In contrast, the present novel delivery system is capable of treating the entire surface of a body cavity due to its solid crystalline structure in a composition selected to provide a mechanically stable foam. The body cavities may be natural or artificial body cavities, created by wounds or surgery.
The usefulness of using foams for the treatment of body cavities is well known and described in Arzhavitina A, Steckel H. “Foams for pharmaceutical and cosmetic application”. Int J Pharm. 2010 Jul. 15; 394(1-2):1-17. doi: 10.1016/j.ijpharm.2010.04.028. Epub 2010 Apr. 29. Foam containing monoacylglycerides are not common. In U.S. Pat. No. 4,684,479 the use of acylmonoglycerides in foams, formation of microbubbles, is described. There is no information on the melting point and the acylmonoglyceride is not in crystalline form. In U.S. Pat. No. 5,554,315 the use of acylmonoglycerides to improve physical properties of foams based on surfactants, polyoxyalkylene ethers are described. In U.S. Pat. No. 5,693,258 the use of acylmonoglyceride polyoxyethylene derivatives for foams is described. The use of acylmonoglycerides alone or their crystals is not mentioned. In U.S. Pat. No. 7,141,237 and U.S. Pat. No. 7,374,747 the use of higher alcohols, C14 to C22, a small alcohol C1 to C6 water and a surfactant for the generation of a temperature sensitive foam is described. In the presentations of the invention no acylmonoglyceride is mentioned and the formulations contain a surfactant based on an ester of laurinmonoglyceride. In U.S. Pat. No. 7,749,488, a foam consisting of ethanol, water, a surfactant, a pH adjusting compound and a propellant is described in the first claim. The surfactant is defined as a compound from the groups of block-co-polymers, fatty acid and/or fatty alcohol etoxylates, polysorbates and glycerol ester etoxylates. A person skilled in the art may add one or several of the surfactants of these groups to the invented composition for the purpose of improving physical properties, but the invention is based on the use of crystalline lipids and their melting at temperatures below 37° C. which is not taught by this patent. In U.S. Pat. No. 8,193,244 the use of C12 monoacylglycerol in combination with long chain dibasic amino acid alkyl ester salts has been claimed as a synergistic antimicrobial combination, which is not relevant for a foam application. The use of C12 acylmonoglcyeride for the treatment of otitis has been described in U.S. Pat. No. 8,476,319 but there is no teaching of the use of the acylmonoglyceride in crystalline form nor its melting.
In U.S. Pat. No. 8,512,723 the use of C12 acylmonoglyceride is described. However, in this patent the product must contain at least 50% of hydrophobic compound and there is no teaching of the use of the acylmonoglyceride in crystalline form and/or its melting. In U.S. Pat. No. 8,586,008 a foam for topical purposes containing various medical agents is presented. The patent teaches that the melting point of this foam can be regulated with the presence of ethanol. In the invented formulation the melting temperature is regulated by the mixing proportions of acylmonoglycerides. The presence of ethanol increases solubility of the acylmonoglycerides is thereby inhibiting the formation of crystals that is important for the properties of the foam. The patent teaches away from using crystals in the formulation.
Monoglyceride lipid crystals comprising hydrogen peroxide are known for external administration, e.g. on the skin, in the form of creams. The hydrogen peroxide is not formulated to be active in the presence of catalases, the products are not suitable for administration into body cavities, e.g vagina, and the formulation cannot adequately fill a body cavity.
In (Tamarkin) WO2011039637 the main claim in this patent application is “A substantially surfactant free foamable composition comprising: a) about 60% to about 95% by weight of a hydrophobic solvent, or about 1% to about 80%) by weight petrolatum and about 15% to about 94% by weight hydrophobic solvent, wherein if combined the total amount of hydrophobic solvent and petrolatum is at least about 60%>by weight”. This patent application does not teach the use of crystalline lipids in a water base to form a foam.
There is a need for improvements in treating infections in body cavities, especially under conditions where classical antibiotics may not be effective and/or where there is a risk for resistance development. There is a need for a product that can be administered immediately upon discovering an infection without any risk of creating antibiotic resistance of the infecting agent and with a high probability of efficient treatment irrespective of the nature the infecting agent, e.g. bacteria, virus, fungi and flagellates.